RESUMO
Several novel 15-membered-ring macrolide agents (azalide 1, triamilides 2 and 3, and the azalide 3,6-ketal 4) were identified as potential antibacterial agents against Mannheimia (formerly named as Pasteurella) haemolytica, Pasteurella multocida, Haemophilus somnus and Actinobacillus pleuropneumoniae, important etiological agents of bovine and porcine respiratory disease. Compound 3 is the major component of the antibiotic tulathromycin. Antibacterial activity against tilmicosin-resistant P. multocida field isolates was also tested. In vitro MIC 50/90 analysis revealed that the four newly synthesized compounds were more potent than tilmicosin against M. haemolytica (4 to approximately 8x), P. multocida (8 to approximately 16x), A. pleuropneumoniae (4x), H. somnus (2x and 16x), and tilmicosin-resistant P. multocida (32x). In time-kill kinetic studies, all four novel compounds and tilmicosin showed bactericidal activity against M. haemolytica, P. multocida and A. pleuropneumoniae at both 4x and 8x MIC. A functional assay using genetically defined mutants revealed that all four novel compounds were poorer substrates for the efflux pump, AcrA/B system, than tilmicosin. A pH study using LPS mutants indicated that the enhanced in vitro potency of the triamilides, particularly compound 3 was mainly due to better penetration of the molecule through the outer membrane. The third amine group at the C-4'' position of the triamilde molecules contributed to this increased membrane penetration by increasing overall basicity. These studies indicate that the four novel compounds have potential as antibacterial agents against bovine and porcine respiratory disease.
Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Macrolídeos/farmacologia , Inibidores da Síntese de Proteínas/farmacologia , Animais , Bovinos , Doenças dos Bovinos/microbiologia , Cinética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Suínos , Doenças dos Suínos/microbiologiaRESUMO
Modification of the cladinose C-4" position via manipulation of the corresponding keto derivatives afforded two stereochemically pure series of compounds. The synthesis and structure determination of these compounds is described within. The in vitro and in vivo biological activity of this novel series of C-4" modified macrolides is also described.
Assuntos
Compostos Aza/síntese química , Compostos Aza/farmacologia , Macrolídeos/síntese química , Macrolídeos/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Compostos Aza/química , Modelos Animais de Doenças , Escherichia coli/efeitos dos fármacos , Hexoses/química , Macrolídeos/química , Camundongos , Testes de Sensibilidade Microbiana , Conformação Molecular , Infecções por Pasteurella/microbiologia , Pasteurella multocida/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Aryl and hetero aryl substituted 3,6-ketals of 15-membered azalide analogues were synthesized and were found to have potent in vitro antibacterial activity against veterinary pathogens, including Staphylococcus aureus and Pasteurella multocida.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/farmacologia , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Animais , Bovinos , Doenças dos Bovinos/microbiologia , Feminino , Hormônio Liberador de Gonadotropina/síntese química , Mastite Bovina/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Pasteurella multocida/efeitos dos fármacos , Pasteurelose Pneumônica/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The stereoselective synthesis of two novel series of tribasic macrocyclic antibiotics with potent in vitro activity against Pasteurella multocida and Escherichia coli strains of bacteria is described. The in vitro activity can be significantly influenced by the nature of the substituents on the C-4" aminoalcohol, with the stereochemistry of the C-4" alcohol playing a less critical role. The effect of substitution and stereochemistry on the in vivo activity in a murine model of respiratory infection is also described.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Animais , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Infecções Bacterianas/virologia , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Indicadores e Reagentes , Macrolídeos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Infecções por Pasteurella/tratamento farmacológico , Infecções por Pasteurella/microbiologia , Pasteurella multocida/efeitos dos fármacos , EstereoisomerismoRESUMO
3,6-Ketals of 15-membered azalide pseudoaglycones are a novel series of macrolide antibiotics. The aromatic derivatives of the azalide 3,6-ketals demonstrated potent antibacterial activities against both Gram-positive and Gram-negative bacteria.